Transferase Inhibitors

Proteins can be modified after translation in the ribosome by the addition of groups such as phosphate, methyl, or acetyl, and larger building blocks such as prenyl and geranyl moieties or polypeptide chains. Kinases transfer phosphate groups from ATP to the hydroxyl groups of Ser, Thr, or Tyr residues or to the imidazole group of His. This switches on the function of the phosphorylated protein substrate. Phosphatases can reverse this step by removing the phosphate group from a phosphorylated amino-acid residue. More than 530 human kinases act as switches in signaling cascades and are attractive as putative drug targets. However, their substrate, ATP, is present in high concentrations in cells. It is recognized by multiple proteins, often with different functions, and kinases are used redundantly. This makes selective competitive inhibition of kinases at the ATP binding site a difficult task. Kinases are rather flexible proteins that adapt to their substrates. The adenine moiety of ATP is recognized by a peptide strand in the hinge region. Next to the ATP binding site are the front and back pockets. They are not involved in ATP recognition, but can be used to confer the necessary selectivity to competing inhibitors. Inhibitors are profiled against the kinase family (kinome) and show either high selectivity for individual members or promiscuous binding to some groups of the kinases on the phylogenetic family tree. Imatinib and its successor nilotinib bind to the inactive conformation of BCR-ABL kinase. They represent a completely new approach to cancer therapy, curing chronic myeloid leukemia by inhibiting the product of a misregulated gene. An allosteric inhibitor has been found to block BCR-ABL kinase by occupying the enzyme’s myristoyl pocket. The bump-and-hole method allows the biological relevance of a target protein to be validated and a class of inhibitors to be optimized. Phosphatases remove phosphate groups from Ser, Thr, Tyr and His residues, thereby inactivating the biochemical function of the substrate protein. Two catalytically distinct classes of enzymes are known to act either by nucleophilic attack on a water molecule highly polarized by two adjacent metal ions, or by nucleophilic attack on a cysteine residue via a pathway similar to that of cysteine proteases. In both cases, the tetrahedral phosphorus atom is attacked. PTP-1B initially appeared to be an ideal target for the treatment of metabolic syndrome because it involves dephosphorylation of insulin receptor kinase. Potent inhibitors of this target with challenging druggability were developed, but lacked sufficient selectivity with respect to another phosphatase, TCPTP. The full-length phosphatase Shp2 is autoinhibited by its N-SH2 domain in the absence of a phosphorylated substrate. This state can be stabilized by an allosteric inhibitor that binds simultaneously to all three domains and “glues” them together. This blocks the formation of the enzymatically active form of the phosphatase. Catechol-O-methyltransferase is a member of the family of methyltransferases that use S-adenosyl-L-methionine as a cofactor for methyl transfer via its sulfonium group. It transfers methyl groups to catecholamines such as dopamine, epinephrine, or norepinephrine. Inhibition of the methyltransferase reaction is achieved by introducing strong electron-withdrawing groups, such as nitro groups, on the aromatic ring of the natural substrates to form substrate-like inhibitors. Farnesyl and geranylgeranyl transferases transfer prenyl anchor groups to protein substrates that have a CAAX sequence at the C-terminus. Inhibitors of farnesyl and geranylgeranyl transferases bind competitively to either the CAAX peptide substrate or the prenyl diphosphate substrate binding site. https://sn.pub/e3r70u